Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages surrounded by a variety of stromal cell types. Understanding cancer etiologies requires evaluating the relationship among cell types during disease initiation and through progression. Genetically engineered mouse (GEM) models facilitate the prospective examination of early oncogenic events, which is not possible in humans. Since most solid tumors harbor aberrations in the pRb network, we developed an inducible GEM approach for the establishment and assessment of carcinoma initiation in a diverse range of epithelial tissues and subtypes upon inactivation of pRb-mediated tumor suppression (Rb-TS). The system allows independent assessment of epithelial subtypes that express either cytokeratins (K) 18 or 19. By Cre-dependent expression of a protein that dominantly inactivates pRb and functionally redundant proteins p107 and p130, neoplasia could be initiated in either K18 or K19 expressing cells of numerous tissues. By design, because only a single pathway aberration was engineered, carcinomas developed stochastically only after long latency. Hence, this system, which allows for directed cell-type-specific carcinoma initiation, facilitates further definition of events that can progress neoplasms to aggressive cancers via engineered, carcinogen-induced and/or spontaneous evolution. To further assess the susceptibility of prostate epithelium to Rb-TS inactivation, we inactivated Rb-TS in K18 and K19 subtypes in prostate using prostate specific Cre line (Pb-Cre4). To our surprise, mouse prostatic intraepithelial neoplasia (mPIN) lesions were initiated in K19 cells, but not in K18 cells at 2 months of age. Addition of PTEN deletion in prostate epithelium accelerated the mPIN to adenocarcinoma and metastasized to lung and other organs in K19 animals, while K18 animals all died from enlarged thymus at 6-10 months of age due to strong K18 expression and low PbCre4 activity in thymic epithelial cells, precluding the analysis of end stage prostate phenotype. Thus, cell subtype tumors are initiated in dictates the histopathological phenotype and onset of tumor development. We are currently assessing the tumors' response to castration in K19 models. Song, Y., Gilbert, D., O'Sullivan, T.N., Yang, C., Pan,W., Fathalizadeh, A., Lu, L., Haines, D., Martin, P., Van Dyke, T. Carcinoma Initiation via Rb Tumor Suppressor Inactivation: A Versatile Approach to Evaluating Epithelial Subtype-Dependent Cancer Initiation in Diverse Tissues, Under review at PLoS One. 08-2013. Y. Song, C. Yang, D. Gilbert, T.N. O'Sullivan, L. Lu, P.L. Martin, and T. Van Dyke. Metastatic Prostate Cancer Initiated in K19 Prostate Epithelial Cells in Genetically Engineered Mouse Model. In Preparation.